rs12949119

Positions:

• chr17-18326138-T-A
• chr17-18326138-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144775.3(SMCR8):​c.*3068T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,044 control chromosomes in the GnomAD database, including 20,274 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (20274 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: SMCR8 NM_144775.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53

Genes affected

SMCR8 (HGNC:17921): (SMCR8-C9orf72 complex subunit) Enables protein kinase binding activity and protein kinase inhibitor activity. Contributes to guanyl-nucleotide exchange factor activity. Involved in negative regulation of macromolecule metabolic process; regulation of TOR signaling; and regulation of macroautophagy. Located in chromatin; cytoplasm; and nucleoplasm. Part of guanyl-nucleotide exchange factor complex. Colocalizes with Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCR8	NM_144775.3	c.*3068T>A		3_prime_UTR_variant	2/2	ENST00000406438.5	NP_658988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCR8	ENST00000406438.5	c.*3068T>A		3_prime_UTR_variant	2/2	1	NM_144775.3	ENSP00000385025	P1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75569 AN: 151926 Hom.: 20237 Cov.: 32

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.480

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.498 AC: 75662 AN: 152044 Hom.: 20274 Cov.: 32 AF XY: 0.494 AC XY: 36749 AN XY: 74324

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.481

Alfa AF: 0.479 Hom.: 2176

Bravo AF: 0.502

Asia WGS AF: 0.340 AC: 1185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.85
DANN	Benign	0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12949119; hg19: chr17-18229452; COSMIC: COSV57398092; COSMIC: COSV57398092;